Tissue-resident memory (TRM) cells are potent mediators of immunity against infectious pathogens in peripheral tissues. Published studies from our laboratory now establish a crucial role for TRM cells in immunity to cancer. We show that immunotherapy-induced CD8 TRM cells mediate immunity to melanoma in the skin, and that autoimmune vitiligo is a key host requirement for generating these durably protective TRM cells. Vitiligo has long been recognized as a positive prognostic factor in melanoma patients. We find that the skin of vitiligo- affected mice provides a hospitable niche for the residence of memory T cells that provide durable, protective, antitumor immunity. We hypothesize that a diverse complement of functional memory T cells in peripheral tissues underlies the durable tumor immunity observed in mice and melanoma patients with vitiligo and other cutaneous inflammatory events. Our first Specific Aim will be to determine the contribution of TRM cells to metastatic tumor protection. Mice with vitiligo also maintain protection against lung metastases, and our preliminary data reveal a distinct population of tumor-specific TRM cells in the lungs of mice with vitiligo. We will test the hypothesis that lung TRM cells and lymphoid TEM cells together prevent metastatic melanoma growth, and define a core transcriptional signature for lung and skin TRM cells. Our second Specific Aim will be to define the tumor antigen specificity of protective TRM recall responses in skin. Our data show that TRM cells in vitiligo- affected skin have specificity for melanocyte/melanoma shared antigens, as well as a model tumor-specific antigen. We will determine how antigen recognition affects T cell function and competition for the TRM niche, and test the hypothesis that TRM cells with specificity for both tumor/self antigens and neoantigens mediate the rejection of melanoma and non-melanoma tumors in the skin. Finally, our third Specific Aim will be to determine the role of antigen-unrelated cutaneous inflammation in promoting TRM responses to melanoma. We will test the hypothesis that melanocyte-unrelated skin inflammation can generate melanoma-specific TRM cells by assessing TRM cell responses in skin biopsies from melanoma patients with vitiligo and other cutaneous inflammatory events. Preclinical work will focus on a therapeutic approach for promoting TRM responses in conjunction with immune checkpoint inhibition. Overall, this project will define the role of resident memory T cells in the immune response to cancer. By demonstrating a fundamental role for TRM cells in host-wide immunity to cancer, these studies are expected to have a transformative impact on the way that immunotherapies are delivered and evaluated.